Clinical Outcome Measures - An Industry Perspective Veronika - PowerPoint PPT Presentation

Clinical Outcome Measures - An Industry Perspective Veronika Logovinsky, MD, Ph.D. On behalf of the EFPIA Working Group 24-25 November 2014 London UK 1

Declaration of Conflicts of Interest Veronika Logovinsky is an employee of Eisai Inc. The presentation is being made on behalf of the EFPIA working group and does not represent the views of Eisai Inc. 2

Key considerations  How can clinical progression and treatment response be measured in Preclinical and Prodromal AD?  Preclinical AD represents asymptomatic stages with or without memory complaints and emerging episodic memory and executive function deficits  Prodromal AD represents pre-dementia stage characterized predominantly by cognitive deficits and emerging functional impairment with disease progression  How can clinical meaningfulness of treatment effects be established in in Prodromal AD?  In Prodromal AD effect on cognition is predominant while effect on function is difficult to measure  How can clinical meaningfulness of treatment effects be established in Preclinical AD?  In Preclinical AD only effect on cognition is likely measurable  Prevention trials will be large and extremely long to show reduction in incidence of disease related cognitive deficits  Lack of established surrogate biomarkers precludes alternatives to clinical outcome measures for all pre-dementia stages (Preclinical and Prodromal AD) 3

Difficult to Measure Change in Prodromal and Preclinical AD Preclinical Prodromal Dementia Cognitive , Functional & Behavioral deficits Memory complaints Cognitive Impairment Mild Moderate Severe aMCI / Prodromal AD Preclinical Emerging functional impairment No apparent symptoms  Prodromal AD: current instruments may o Have suboptimal sensitivity to clinical progression and treatment o Have challenges measuring subtle functional impairments o Have been inconsistently used in Prodromal AD clinical trials and lack historical data  Preclinical AD: Episodic Memory and Executive Functioning deficits emerge o No measures established in interventional trials o Wealth of alternative measures that lack trial data  Prevention trials will be large and extremely long to show reduction in disease incidence o Need very high sensitivity to emerging clinical symptoms 4

Different Outcomes: Performance-Based Outcome Measures Established / De Novo Psychometrically-Derived Performance-Based Outcome Measures  Available measures, but have not been utilized in interventional trials  Designed to meet established reliability and validity standards  Reliability – Test-retest; Alternative-Form; Inter-rater reliability  Validity – Construct; Criterion; Content; Predictive; Face (Ecological); Convergent; and Discriminant  Aim to focus on cognitive domains affected early in disease  Episodic memory and timed Executive Functioning  Drawbacks - lack of systematically collected trial data needed for power analyses, modeling purposes and understanding of treatment response  Need to be included in future trials → will take years before “established” 5

Different Outcomes: Patient-Reported Outcome (PRO) Measures  PRO Scales ~ De Novo Scales (no established PRO scales in Prodromal AD/MCI or AD dementia)  The Cognition Working Group of the Critical Path Institute’s Patient-Reported Outcome Consortium seeks to develop a PRO instrument to be qualified by the FDA as an efficacy endpoint in clinical trials of patients with MCI due to AD  capture the patient’s perspective on specific aspects of functioning  contribute to the description of disease progression and the measurement of treatment effects  Current status of C-Path PRO: qualitative research phase Main challenges in developing PRO measures for Prodromal AD/MCI patients  Specification of a recall period for the instrument  Frequency of individual activities highly variable  Variability of engagement in individual activities  Preservation of insight (critical in ensuring the reliability and validity of patient reports) in population with progressing cognitive deficits:  Crucial to understand where along continuum of progression to AD dementia patients lose ability to accurately self-report  There is uncertainty about method(s) for determining adequacy of patient insight 6

New Outcome Measures in Preclinical and Prodromal AD  Improvement of established scales – focus on sensitivity • Also aim to increase responsiveness to therapy • Preserve clinical meaningfulness  De Novo Scales –  focus on theoretical constructs • Foundation in psychometric principles (e.g., construct validity) • Based on assumptions on clinical meaningfulness (e.g. face validity)  Drawback - lack of historical data - resource-intensive & time-consuming  focus on standardization and ease of use • Computerized tests – emphasis on sensitivity and potential for remote use  Drawback - lack of historical data; unclear support for clinical meaningfulness  All new outcome scales should be subject to standardized validation process with clearly specified requirements  It is essential to standardize characteristics of target population when comparing performance of new outcomes across different trials with data sharing being key to this process 7

Issues Around Clinical Meaningfulness in Preclinical and Prodromal AD At early stages AD is primarily disease of cognition:  cognitive decline precedes and predicts functional decline (Zahodne et al. 2013; Liu ‐ Seifert et al. 2014a)  effect on cognition should be important consideration in assessment of clinical meaningfulness Additional information can be combined with results on specific clinical outcome in support of clinical meaningfulness:  Treatments aimed at the underlying pathophysiology of AD should slow clinical decline and the effect should grow over time  This may be demonstrated by an increasing magnitude of effect, point difference over time, or percent reduction in decline  Biomarkers of underlying AD pathology may be clinically meaningful  Time-to-event or responder analyses, have been suggested as conceptually appealing measures of clinically meaningfulness  associated with practical difficulties, such as dichotomizing 2 disease stages (pre-dementia vs. dementia) that exist along a continuum (FDA 2013) or defining new, standardized and agreed upon events that signal clinical progression 8

Efforts to Develop Clinical Measures for Prodromal AD  Tools developed by industry & academia for early stage AD  Use existing data sets and established measures  Validity and clinical meaningfulness “borrowed” by using established scales for dementia AD  Select elements responsive to clinical progression in this disease stage  Emphasizing items sensitive in Prodromal AD  ADAS-Cog alone or additive scales by combining ADAS-Cog with items from other instruments (CDR-SB, MMSE, FAQ etc.)  Modifications to increase sensitivity to decline and treatment effect  Improved weighting provides further optimization  Results - Composite Clinical Endpoint with weighted items from established scales, e.g. ADAS-Cog, CDR-SB and MMSE  These composites converge on selected items

Progression of Composites for Prodromal AD 1 - Individual Efforts 2008 – Composite & Cognition Scores developed by Industry & Academia onwards . 2 - Start of cooperation 2009 – ADNI PPSB (Industry Group) ADAS-Cog Plus Working Group 2013 3 - Harmonization of Efforts ADNI PPSB Data Mining Session & Clinical End Points Working Group 2012 – onwards 4 - Regulatory Qualification CAMD (C-Path Institute): pCOA Project 2013 – 1. Data analyses on candidates selected in PPSB CEWG 2016 2. Submission Letter of Intent to FDA and EMA – Stage 1 3. Submission of Qualification request to FDA and EMA – Stage 2 4. Aim for approval of new Instrument (as primary EP)…… 10

Emerging Outcomes for Preclinical AD Developing Clinical Outcome Tools  De novo scales – highly sensitive to very early symptoms  Computerized tests – lack clinical meaningfulness  Rely on ongoing observational studies to validate measures  Drawbacks - lack of historical data; lack of trial data, no link to clinical meaningfulness data  Years before “established” Biomarkers of Pathophysiological Progression  Surrogates for clinical measures  Drawbacks – lack of strong candidate biomarkers as outcome measures, less so for early stage of disease, no correlation established between clinical outcome and biomarkers data in trials 11